Repeated administration of cocaine to rats produced behavioral sensitization but did not alter dopamine levels or dopamine metabolites in response to cocaine challenge as revealed with microdialysis procedures. In vivo microdialysis revealed differential effects of cocaine on dopamine release following direct applications to the frontal cortex, nucleus accumbens, or striatum. Acute ECS enhanced the release of dopamine in the frontal cortex but not any other region, while chronic ECS appeared to elevate basal dopamine levels in all three dopamine terminal areas. Morphine applied to the striatum or nucleus accumbens increased the release of dopamine, with the latter structure being more sensitive. Morphine applied unilaterally to the substantia nigra (SN) or ventral tegmental area decreased dopa- mine release in the ipsilateral striatum and nucleus accumbens, respectively. The kappa opiate agonist U-50,488 increased nociceptive thresholds in a stereoselective manner following systemic injections. The inactive and active enantiomers were equally effective in modifying nociceptive thresholds following i.v. injections, indicating that the analgesic effects of this class of opiates are mediated through the spinal cord or through peripheral mechanisms. No tolerance developed to the depressant effects of U-50,488 on locomotor activity, while the excitatory effects increased in intensity with repeated injections. The mesolimbic dopamine system does not mediate the excitatory effects of kappa opiates. Diuresis induced by kappa agonist is mediated through the CNS. PCP-induced activation of the SN resulted in both increases and decreases in the metabolic activity of diencephalic and mesencephalic. Alterations in the metabolic activity of structures caudal to the SN are related to the motor assymetrics produced by intranigral PCP. PCP and other noncompetitive NMDA antagonists altered metabolic activity in a variety of structures. Injections of morphine into the periaqueductal gray matter as well as electrical stimulation of this structure produced a suppression of NK cell activity. Opiate receptors in the SN are located on striato-nigral terminals.